Glucokinase (GK) is one of four hexokinases found in mammalian animals. Hexokinases catalyze a conversion of glucose into glucose-6-phosphate which is the first step of glucose metabolism. GK is localized mainly in hepatic parenchymal cells and pancreatic β cells, and plays an important role in whole body glucose homeostasis as a rate-controlling enzyme for glucose metabolism in these cells. The hepatic parenchymal and pancreatic forms of the enzyme are different in N-terminal 15 amino-acid sequence depending on the difference of each splicing, but are functionally indistinguishable. Three hexokinases except GK are saturated in enzymatic activity at a glucose concentration below 1 mM, but Km of GK is 8 mM, which is within a physiological range of blood-glucose levels. Therefore, GK-mediated intracellular glucose metabolism is activated as the concentration of blood glucose increases from normal level (5 mM) to postprandial level (10 to 15 mM). A hypothesis that GK functions as a glucose sensor of pancreatic β cells and hepatocyte has been proposed (Nonpatent Document 1). Thereafter, it has been clarified that GK actually plays a definitely important role in whole body glucose homeostasis according to the results of GK genetically-modified animal studies. GK KO mice die soon after birth (Nonpatent Document 2), while both normal and diabetic mice overexpressing GK showed lower glucose level than wild type animals (Nonpatent Document 3).
In maturity-onset diabetes of the young type II (MODY-2), which is one of the genetically determined diabetes, loss of function mutations in GK has been found and it is thought that the low GK activity in MODY-2 results in hyperglycemia (Nonpatent Document 4). On the other hand, families having a GK mutation with increased enzymatic activity have been found and these people have shown hypoglycemia (Nonpatent Document 5). Accordingly, GK is believed to be a glucose sensor and to play an important role in maintenance of glucose homeostasis in human as well. It is expected that a GK activating compound has an insulinotropic action in β cells, an enhancing effect of glucose uptake in liver and an inhibitory effect of hepatic output since such a compound activates a GK sensor system, and hence, it is believed that such a compound is useful for treating, for example, Type 2 diabetes.
Recently, it has been shown that a pancreatic β cell type glucokinase is distributed locally in feeding center (Ventromedial hypothalamus, VMH) in rat brain. About 20% of nerve cells in VMH are referred to as glucose responsive neurons and it has been thought from the past that they play important roles in controlling of body weights. An intracerebral administration of glucose in rat decreases food intake, but on the contrary, rat becomes overeating by an intracerebral administration of a glucose analog glucosamine, which cause a suppression of glucose metabolism. In electrophysiological experiments, glucose responsive neurons in VMH are stimulated when glucose increases from 5 to 20 mM, and their activities are blocked by glucosamine or the like (Nonpatent Document 6). It is thought that a glucose sensor mechanism of VHM is similar to that of pancreatic β cells. Therefore, a GK activating substance has a possibility of ameliorating obesity which is one of the major problems in Type 2 diabetes as well as correcting hyperglycemia.
Accordingly, a compound having a GK activation effect is useful as a therapeutic and/or preventive agent for diabetes, or chronic complication of diabetes such as retinopathy, nephropathy, neuropathy, ischemic heart disease or arteriosclerosis, or even obesity.
The compound having a GK activation effect includes, for example, pyridinecarboxylic acid derivatives (Patent Document 1), 2-pyridine-carboxamide derivatives (Patent Document 2), heteroarylcarbamoyl-benzene derivatives (Patent Document 3), heteroaryl derivatives (Patent Document 4), substituted arylcyclopropylacetamide derivatives (Patent Document 5), 5-substituted pyrazine or pyridine derivatives (Patent Document 6), substituted (thiazol-2-yl)amide or sulfonamide derivatives (Patent Document 7), substituted phenylacetamide derivatives (Patent Document 8) or amide derivatives (Patent Document 9).    [Patent Document 1] WO05/044801    [Patent Document 2] WO04/081001    [Patent Document 3] WO04/076420    [Patent Document 4] WO04/063194    [Patent Document 5] WO04/063179    [Patent Document 6] WO04/052869    [Patent Document 7] WO04/050645    [Patent Document 8] WO03/095438    [Patent Document 9] WO03/055482    [Nonpatent Document 1] American Journal Physiology, 247 (3Pt2), 1984, p. 527-536    [Nonpatent Document 2] Cell, 83, 1995, p. 69-78    [Nonpatent Document 3] Proceedings of the National Academy of Sciences of the U.S.A., 93, 1996, p. 7225-7230    [Nonpatent Document 4] Nature Genetics, 356, 1992, p. 721-722    [Nonpatent Document 5] New England Journal of Medicine, 338, 1998, p. 226-230    [Nonpatent Document 6] Diabetes, 48(9), 1999, p. 1763-72